This invention is directed to .alpha. and .beta.-ribonucleosides of substituted pyrimido[5,4-d]pyrimidines and to the use of these compounds in treating malignant tumors in vivo. A novel synthesis for preparing these compounds and other related compounds is further disclosed.
While the arsenal of chemotherapeutic agents for treating neoplastic diseases includes a number of clinically useful agents, control of malignant tumors in warm blooded animals still remains a much sought after goal.
Recent molecular biology and biochemistry studies of purine and purine nucleoside analogs showing potent antiviral and antitumor activity have uncovered a number of new potential targets. The pyrimido[5,4-d]pyrimidine ring system has attracted considerable attention in recent years as the deaza-analog of the naturally occurring antibiotics toxoflavin and fervenulin. Dipyridamole, a pyrimido[5,4-d]pyrimidine derivative, has shown coronary vasodilator properties. The synthesis of the naturally occurring exocyclic aminonucleoside clitocine has also been reported.
The synthesis and the biological properties of an unusual exocyclic aminonucleoside, 4-amino-8-(.beta.-D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (hereinafter alternately referred to as ARPP) has also been reported, see Westover et al. J. Med. Chem. (1981), 24, 941-946. ARPP has shown antiviral activity for DNA and RNA viruses in cell culture by inhibiting viral protein synthesis. ARPP exhibits immunosuppressive activity and inhibits the growth of L1210 leukemia in mice.
Molecular mechanics calculation of ARPP and certain related nucleosides has shown that their conformational behavior is very similar even when groups like chloro or amino are introduced at positions 2 and/or 6. Other studies on the modification of the glycon moiety of ARPP resulted in the loss of antiviral and antitumor activity, see Srivastava et al. J. Med. Chem. (1981), 24, 393-398.
In view of the inability of current cancer chemotherapeutics to successfully control all neoplastic diseases, it is evident that there exists a need for new and additional cancer chemotherapeutic agents.
Further, there exists a need for new and better preparative procedures for the synthesis of pyrimido[5,4-d]pyrimidines nucleosides.